Calixarenes are complex compounds containing a [1.sub.n ] metacyclophane framework. Although some applications for some types of calixarene compounds have been developed, research into calixarene chemistry is still progressing. See Gutsche, Calixarenes, Royal Soc. Chem., 1989. The present inventors have synthesized new calixarene derivatives, and have developed an important application for some calixarene derivatives as chloride channel blockers.
All cell types have chloride channels. Chloride ion channels are transport proteins that allow for the rapid (i.e., 10.sup.6-10.sup.8 ions/second) entry and exit of chloride across the plasma membrane. Based on their distribution in various cell types and their biophysical as well as functional diversity, chloride channels may serve as molecular targets for effective pharmaceuticals in a variety of applications.
Chloride channels subserve a wide variety of specific cellular functions. It is known that abnormal chloride permeability in skeletal muscles plays a part in some forms of myotonia. Thus, chloride channels contribute to the normal function of skeletal and smooth muscle cells. Additionally, the contribution of chloride channels in fluid and electrolyte secretion is well documented in the physiology of epithelia. Further, patients suffering from cystic fibrosis exhibit effects caused by too few open chloride channels, while patients suffering from diarrhea demonstrate the acute effects of too many open chloride channels.
Thus, in general, chloride channel modulators may serve as effective pharmaceuticals for treating respiratory, cardiovascular and gastrointestinal disorders. Specific therapeutic applications for chloride channel modulators include the treatment of asthma, hypertension, cancer, diabetes, ischemia, muscle fatigue, edema, diarrhea, cystic fibrosis and myotonia.
Only a few substances have been found that affect chloride channels. Chloride channel blockers that have been developed include 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), 2-[(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)ox y]acetic acid (IAA-94) and 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). See, Singh et al., "Colonic Cl Channel Blockade by Three Classes of Compounds", Am. J. Physiol. 261 (Cell Physiol. 30): C51-C63, 1991.
Although various carboxylic and sulfonic organic acids have been tested as chloride modulators, heretofore there has not been developed a highly potent and specific chloride channel modulator causing long-lived block periods at low concentrations.